Xuelian Cui1,2, Yixuan Wang1,2, Weiqiang Lan1,2, Shuhao Wang1,2, Ying Cui1,2, Xianglan Zhang3,4, Zhenhua Lin1,2, Junjie Piao5,6. 1. Department of Pathology & Cancer Research Center, Yanbian University, Yanji, 133002, China. 2. Key Laboratory of the Science and Technology Department of Jilin Province, Yanji, 133002, China. 3. Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, South Korea. 4. Department of Pathology, Yanbian University Hospital, Yanji City, China. 5. Department of Pathology & Cancer Research Center, Yanbian University, Yanji, 133002, China. piaojunjie@ybu.edu.cn. 6. Key Laboratory of the Science and Technology Department of Jilin Province, Yanji, 133002, China. piaojunjie@ybu.edu.cn.
Abstract
BACKGROUND: Sparc/osteonectin, cwcv and kazal-like domain proteoglycan 1 (SPOCK1) has been reported to function as an oncogene in a variety of cancer types. Increasing evidence suggests that SPOCK1 contributes to the metastatic cascade, including invasion, epithelial-mesenchymal transition (EMT) and micro-metastasis formation. As yet, however, the underlying mechanism is not clearly understood. Here, we evaluated the expression and clinicopathological significance of SPOCK1 in primary pancreatic cancer (PC) specimens and explored the mechanisms underlying SPOCK1-mediated PC cell growth and metastasis. METHODS: The clinical relevance of SPOCK1 was evaluated in 81 patients with PC. The effect of SPOCK1 on proliferation, cell cycle progression, EMT and metastasis was examined in vitro and in vivo. The molecular mechanisms involved in SPOCK1-mediated regulation of NF-κB-dependent EMT were assessed in PC cell lines. RESULTS: We found that SPOCK1 expression was increased in PC tissues and was associated with lymph node metastasis. Silencing or exogenous overexpression of SPOCK1 markedly altered the proliferation of PC cells through cell cycle transition. Overexpression of SPOCK1 promoted PC cell migration and invasion by regulating EMT progression. Moreover, we found that SPOCK1 contributes to EMT and metastasis by activating the NF-κB signalling pathway via direct interaction with IκBα. After NF-κB pathway inhibition by BAY11-7082, we found that PC cell motility and EMT induced by SPOCK1 were reversed. CONCLUSION: From our data we conclude that SPOCK1 promotes PC metastasis via NF-κB-dependent EMT by interacting with IκBα. This newly identified mechanism may provide novel clues for the (targeted) treatment of PC patients.
BACKGROUND: Sparc/osteonectin, cwcv and kazal-like domain proteoglycan 1 (SPOCK1) has been reported to function as an oncogene in a variety of cancer types. Increasing evidence suggests that SPOCK1 contributes to the metastatic cascade, including invasion, epithelial-mesenchymal transition (EMT) and micro-metastasis formation. As yet, however, the underlying mechanism is not clearly understood. Here, we evaluated the expression and clinicopathological significance of SPOCK1 in primary pancreatic cancer (PC) specimens and explored the mechanisms underlying SPOCK1-mediated PC cell growth and metastasis. METHODS: The clinical relevance of SPOCK1 was evaluated in 81 patients with PC. The effect of SPOCK1 on proliferation, cell cycle progression, EMT and metastasis was examined in vitro and in vivo. The molecular mechanisms involved in SPOCK1-mediated regulation of NF-κB-dependent EMT were assessed in PC cell lines. RESULTS: We found that SPOCK1 expression was increased in PC tissues and was associated with lymph node metastasis. Silencing or exogenous overexpression of SPOCK1 markedly altered the proliferation of PC cells through cell cycle transition. Overexpression of SPOCK1 promoted PC cell migration and invasion by regulating EMT progression. Moreover, we found that SPOCK1 contributes to EMT and metastasis by activating the NF-κB signalling pathway via direct interaction with IκBα. After NF-κB pathway inhibition by BAY11-7082, we found that PC cell motility and EMT induced by SPOCK1 were reversed. CONCLUSION: From our data we conclude that SPOCK1 promotes PC metastasis via NF-κB-dependent EMT by interacting with IκBα. This newly identified mechanism may provide novel clues for the (targeted) treatment of PC patients.
Authors: Marta Tellez-Gabriel; Xavier Tekpli; Trine M Reine; Beate Hegge; Stephanie R Nielsen; Meng Chen; Line Moi; Lisa Svartdal Normann; Lill-Tove R Busund; George A Calin; Gunhild M Mælandsmo; Maria Perander; Achilleas D Theocharis; Svein O Kolset; Erik Knutsen Journal: Front Oncol Date: 2022-04-14 Impact factor: 5.738